Diabetes mellitus is a disorder of glucose regulation with accumulation of glucose in the blood. It is a major public health problem affecting 285 million people across the world and this number is expected to be over 450 million by 2030 (Wild, et al., Diabetes care, 27:1047-1053 (2004). The malfunction of glucose regulation arises from 1) insufficient secretion of insulin due to autoimmune-mediated destruction of pancreatic, a-cells (type 1 diabetes) or 2) disorders of both insulin resistance and secretion (type 2 diabetes) (Pickup, et al., Diabetes Metab Res Rev, 24: 604-610 (2008); Stumvoll, et al. Lancet, 365:1333-1346 (2005); and Kahn, Diabetes 43:1066-1084 (1994).
Multiple subcutaneous insulin injections and regular monitoring of blood glucose levels are thus essential to sustain life for type 1 diabetic patients and some type 2 diabetic patients (Owens, et al., Lancet, 358:739-746 (2001). However, such self-administration is painful and requires an indispensable commitment of patients. More importantly, this treatment, known as open-loop insulin delivery, does not maintain normoglycemia upon the blood glucose fluctuation (Jeandidier, et al., Adv Drug Deliv Rev, 35:179-198 (1999); Owens, et al., Nat Rev Drug Discov, 1:529-540 (2002)). Lack of tight control of glucose closer to the normal level accounts for many chronic complications such as limb amputation, blindness and kidney failure and often resulted in risks of fatal hypoglycemia (N Engl J Med., 329:977-986 (1993). Therefore, an artificial pancreas-like synthetic closed-loop device able to continuously and intelligently release insulin with the response to blood glucose levels is highly desirable (Kumareswaran, et al. Expert Rev Med Devices, 6:401-410 (2009); Ravaine, et al., J. Control Release, 132:2-11 (2008)). A straightforward strategy is to integrate a glucose monitoring moiety and a sensor-triggered insulin releasing moiety into one system (Ravaine, et al., J. Control Release 132:2-11 (2008)).
A glucose oxidase (GOx) based system which is made of a compartment limited by a semipermeable, ionically charged membrane, containing insulin, glucose oxidase and catalase is described for example in U.S. Pat. No. 4,364,385 to Lossef, et al. WO 06/088473 describes an insulin delivery system in which glucose oxidase, catalase, and insulin are entrapped in, dispersed within, covalently bonded to or embedded within nanospheres to generate a glucose-responsive insulin-delivery vehicle. Glucose Oxidase has also been immobilized onto pH-sensitive hydrogels (Podual, J. Con. Rel. 67:9-17 (1999); Ravaine, J. Controlled Rel., 132:2-11 (2008)). The conversion of glucose to gluconic acid, catalyzed by glucose oxidase, lowers the pH affecting the swelling of pH sensitive hydrogels. This swelling allows a release of insulin in response to an increase in glucose concentrations in the immediate environment.
To effectively control diabetes and prevent hypoglycemic complications, it is desirable to administer insulin in a manner that precisely matches the physiological needs at any given moment. Known hydrogel glucose oxidase-dependent systems suffer from several limitations. For example, hydrogel systems exhibit very long glucose response times. Ravaine, et al., J. Controlled Rel., 132:2-11 (2008). Thus, there still is a significant need for insulin that can become physiologically available as a result of changes in the body's glucose levels.
It is therefore an object of this invention to provide an insulin delivery system that is responsive to changing glucose concentrations at or near physiological pH.
It is also an object of the present invention to provide a method of making a glucose sensitive insulin delivery system that is responsive to glucose concentrations at or near physiological pH.
It is a further objection of the present invention to provide a method of controlling blood glucose levels in a patient in need thereof.